Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder which severely effects cognitive function and other behavioral aspects such as executive function and language skills. AD will become world's largest economic healthcare burden over the coming decades. AD is thought to affect 10% of the population over 65 years of age and much more for those over age 80, with the numbers continuing to increase with longevity. Current U.S. estimates on the number of patients suffering from the disease range from three to five million, with an annual estimated cost of over $100 billion dollars. It is estimated that by 2050 the number of patients with AD could be as high as 25 million. This disease not only presents an economic burden but there cannot be a value attached to the emotional burden for the family and friends of the disease who have to provide care for the patients after cognitive dysfunction sets in. Many of the patients continue to live long lives despite the cognitive dysfunction. Despite this severe unmet need, the current marketed drugs are useful only in treating the symptoms of the disease and do not intervene in disease causing mechanism(s) which could stop or reverse the disease.
The disease was first described in 1907 by Alois Alzheimer and is characterized by a progressive loss of neurons and synapses with the presence of large numbers of extracellular amyloid plaques. The dominant scientific theory for genesis of AD is called “amyloid hypothesis” (See Science, 2002, 297(5580):353-6). According to this beta-amyloid cascade hypothesis, the accumulation of beta-amyloid (Aβ) peptides as amyloid plaques in the patient's brain is the primary triggering event in the pathogenesis of Alzheimer's disease (AD). Amyloid plaques are formed by excess production of amyloid beta peptides (Aβ) primarily by neurons. Both extracellular and intracellular accumulation of Aβ initiates a cascade of events including synaptic and neuritic injury, microglial and astrocytic activation (inflammatory response), altered neuronal ionic homeostasis, oxidative damages, changes of kinases/phosphatases activities, formation of NFTs, and finally cell death. Visible pathological changes such as amyloid plaque formation and neurofibrillary tangles (NFTs) are a consequence of Aβ deposition.
Amyloid beta peptide (Aβ) is generated during the proteolytic processing of the parent beta-amyloid precursor protein (APP). APP is a transmembrane protein with domains spanning the membrane. The membrane spanning domains are hydrophobic and the cleavage of this region generates hydrophobic peptides called Aβ peptides (See Trends Cell Biol. 1998, 8:447-53). The enzymatic cleavage of APP is catalyzed by a set of enzymes called alpha-, beta-, and gamma-secretases (See J Clin Invest. 1999, 104:1321-7). Peptides generated by proteolysis can either be non-amyloidogenic meaning they do not form plaques or they can be amyloidogenic which means they aggregate and form clumps (oligomers of various sizes) and eventually plaques. The alpha-secretase mediated enzymatic cleavage releases non-amyloidogenic peptides considered harmless. The beta-secretase and gamma-secretase working in tandem generate Aβ40 and/or Aβ42. Aβ42 is neurotoxic and more hydrophobic than Aβ40, thus it has stronger tendency to oligomerize and aggregate.
The strongest evidence for a pathogenic role of Aβ peptides in Alzheimer's comes from human mutations in APP and presenilin, the enzyme complex component of gamma-secretase. The majority of known APP and presenilin mutations responsible for familial early onset AD affect APP processing causing overproduction of Aβ peptides, especially Aβ42. Given the acceptance that generation of Aβ42 is fundamental to plaque formation, this has led to attempts to develop therapies based upon blocking the generation of Aβ42. In addition several in vitro and in vivo studies using models of Alzheimer's have also supported a role for production of Aβ peptides being a causative event. Therefore, several strategies are being employed by the pharmaceutical industry to decrease the production of this peptide and some of them are as follows (Annu Rev Pharmacol Toxicol. 2003, 43:545-84; J Clin Invest. 2003, 111:11-18):                a) Inhibition of β- or γ-secretase by small molecular weight compounds        b) Removal of Aβ42 peptides by designing active or passive vaccines to this peptide        c) preventing Aβ42 aggregation and toxicity by small molecule agents        
Niacin (Nicotinic acid) has been used for decades to treat hyperlipidemia. In particular its ability to raise the plasma HDL cholesterol levels has led to an increase in its pharmacological use (See Am J Cardiol. 2007, 100 (11A):S53-61). Niacin also has modest effects on triglycerides and LDL cholesterol. The clinical use of niacin is somewhat limited due to harmless but unpleasant side effect, a cutaneous flushing phenomenon which causes skin redness and itching. Nevertheless niacin currently remains to be the only agent on the market shown to definitely raise plasma HDL.
Niacin has been well known as a vitamin (vitamin B3) and used as drug or nutritional supplement for pellagra. However, phenolic ester hybrids of niacin or cocrystals of such hybrids with cocrystal formers like eugenol and oxalic acid or physical combination of niacin with other small molecule potentiating agents as pharmaceutical compositions for reduction of Aβ42 have not been disclosed previously.
While there is wealth of information on niacin's pharmacological effects on cholesterol and triglycerides, its use as a therapeutic for Alzheimer's has not been systematically studied. Specifically there is no prior art that reports the use of niacin alone or in combinations or niacin esters or cocrystals of niacin esters for reduction of Aβ42. There is one clinical study which reports that niacin consumption in the diet decreases the incidence of Alzheimer's (See J. Neurol Neurosurg Psychiatry, 2004, 75:1093-1099). However there is no mention in this study of how and why niacin could be having these effects. U.S. Pat. No. 4,336,258 relates to phenolic esters of eugenol and N-heteroarylcarboxylic acids, including nicotinic acid for use in stomatology drawing different utility for the combination. However, this patent neither discloses cocrystals of eugenol ester of niacin nor utility in Alzheimer's disease. Similarly, eugenol derivatives as potent lipoxygenase inhibitors has been disclosed in Sedeghian et al (See Biorganic and Med Chem. 2008, 16(2):890-91) for utility other than Alzheimer's disease. Also, effects of eugenol on the central nervous system has been disclosed by Yosifumi Irie (See Current Bioactive Compound, 2006, 2:57-66). However a combination of niacin and eugenol as a physical mixture or as an ester hybrid or as a cocrystal of the ester hybrid as a method to reduce Aβ42 and for treatment of Alzheimer's has hitherto not been disclosed.
There thus remains a need to conduct a systematic study of niacin alone or in combination with other small molecules to discover novel compositions endowed with a property of reducing Aβ42, its deposition, accumulation, and plaque formation and having therapeutic effect in treating Alzheimer's disease, dementia, and mild cognitive impairment.